A USF Health preclinical study suggests that kappa-opioid antagonists offer a potential treatment to help alcohol-dependent patients cut back or quit drinking

TAMPA, Fla. (March 9, 2022) — As heavy or frequent alcohol use escalates, some people continue to drink despite increasingly negative consequences such as poor job or school performance, unraveling family or personal relationships and declining physical health.

Impaired working memory, a common problem for those with alcohol use disorder (AUD), can interfere with recovery and disease management, and contribute to the risk of relapse. Working memory is one of the processes of executive function, a set of high-level mental skills (also encompassing flexible thinking and self-control) needed to learn and to manage daily life.

“People with severe alcohol dependence have reduced ability to make sound decisions, or good choices,” said Brendan Walker, PhD, a professor of psychiatry and behavioral neurosciences at the University of South Florida Health (USF Health) Morsani College of Medicine. “They ignore the problems created by excessive drinking and give up things of importance to satisfy their craving to drink more.”

Dr. Walker studies the biological brain changes that drive addictive behaviors with the aim of finding ways to improve treatment outcomes. A major obstacle to recovery, even months or years after rehabilitation and prolonged abstinence, appears to be physical changes in neurotransmitters and their receptor targets as the brain adapts to abuse of alcohol or other drugs.

Dr. Walker’s laboratory and others have focused on the interaction of alcohol-induced “feel bad” brain peptides (neurotransmitters) known as dynorphins that bind with kappa-opioid receptors (KORs), naturally occurring receptors for opioids in brain cells.

Now, for the first time, a preclinical study led by Dr. Walker shows that dysregulated KORs in the brain’s medial prefrontal cortex region (part of the frontal lobe) contribute to working memory deficiencies in alcohol dependence. Furthermore, the researchers discovered that a compound used to block KORs (an antagonist) alleviated these working memory deficits and may help restore “normal” executive function in those with severe AUD, Dr. Walker said.

The USF Health findings were reported Jan. 20, 2022, in Addiction Biology.

Study principal investigator Brendan Walker, PhD,  a neuroscientist at the USF Health Morsani College of Medicine, studies biological brain changes that drive addictive behaviors.

“Collectively, our research is helping establish that targeting the dynorphin-KOR system could be a viable treatment strategy for managing the hallmark symptoms of alcohol dependence — increased motivation for drinking, increased negative emotional states and compromised executive function (decision-making),” said Dr. Walker, the study’s principal investigator.

Earlier preclinical studies looked at how abnormal regulation of the dynorphin-KOR system in another brain region called the amygdala increases both motivation for alcohol consumption and negative emotional states like depression and anxiety that are amplified during sudden withdrawal from drinking.

In a series of experiments, the USF Health researchers used a rat model mimicking severe human AUD, which was induced by cycles of intoxication (long-term intermittent ethanol vapor exposure) and alcohol withdrawal (exposure to air only). This group of alcohol-dependent rats was compared with two other groups: nondependent rats (a model mimicking social drinking in humans) and alcohol-naïve rats (a control group never exposed to ethanol vapor.) All were trained and tested in a working memory task (delayed nonmatching-to-sample task) involving a T-maze.

Among the key findings:

– The alcohol-dependent rat model the researchers developed proved very effective for measuring working memory deficits.

– Medial prefrontal cortex KORs in the alcohol-dependent rats were overactivated (abnormally increased) in dependence, compared to those same opioid receptors in the nondependent and alcohol-naïve rats. This dysregulation of the dynorphin-KOR system in a brain region critical for the control of working memory correlated with worse working memory performance by the alcohol-dependent rats during acute withdrawal.

– When researchers stimulated KORs in the medial prefrontal cortex of nondependent rats with a KOR agonist mimicking dynorphin, they were able to produce profound working memory deficits like those observed in alcohol-dependent rats.

– Conversely, administering KOR antagonist norbinaltophimine (nor-BNI) to block activation of the brain KORs significantly reduced alcohol-induced impaired working memory. Alcohol-dependent rats showed working memory performance comparable to the nondependent rats.

Brain slice image showing the medial prefrontal cortex (mPFC), a region critical for the control of working memory | Courtesy of Paxinos and Watson, 2005

More studies are needed, including in humans, but previous laboratory research has already shown that KOR antagonists curb the desire to excessively consume alcohol and the negative emotions that can drive self-medication with alcohol. This latest USF Health study suggests such a compound also holds promise for restoring executive function needed for people to make better decisions about their alcohol intake and improve their quality of life, Dr. Walker said.

There is “no magic bullet” for AUD, Dr. Walker emphasized, but identifying and developing one medication that alleviates multiple symptoms could make it easier for patients to cut back or quit drinking when combined with cognitive behavioral therapy.

The USF Health study was supported by a grant from the National Institute of Alcohol Abuse and Alcoholism (NIAAA).

Alcohol is one of the most common forms of substance abuse and a leading cause of preventable deaths and disease, killing nearly 100,000 Americans yearly. In 2019, almost 15 million people ages 12 and older in the U.S had alcohol use disorder, according to the NIAAA.

The USF Health neuroscientist aims to translate his research on kappa opioid receptors into personalized treatments for alcoholism and other addictive disorders

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When USF Health neuroscientist Brendan Walker, PhD, was a teen in California at the height of the 1980s crack epidemic, several of his friends who were top intellects and accomplished athletes grew increasingly dependent on cocaine and alcohol. Some died from their addictions.

The painful loss of friends he grew up with started his journey toward a research career seeking to understand the neurobehavioral systems that drive addiction. “I wondered what could be so powerful about drugs of abuse, including alcohol, that would take over someone to the point where they lost their life,” he said.

Dr. Walker, a professor in the Department of Psychiatry and Behavioral Neurosciences, joined the USF Health Morsani College of Medicine in June 2019.

Brendan Walker, PhD, in his laboratory at the USF Health Department of Psychiatry and Behavioral Neurosciences. Dr. Walker’s group focuses on the long-lasting negative reinforcement aspects of heavy alcohol use in the brain, which can make giving up drinking difficult.

Backed by a five-year, $1.79-million R01 grant  from the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, his laboratory primarily studies the role of kappa opioid receptors in the transition to alcohol dependence. His long-term goal is to turn those discoveries into targeted medications and gene therapies for addictive disorders leading to devastating social, occupational and health consequences.

Historically many researchers have paid more attention to the positive reinforcement effects of alcohol and drugs — particularly the interaction in the brain of peptides known as endorphins with the mu opioid receptors. Endorphins are natural “feel good” chemicals (neurotransmitters) that can relieve stress, boost mood and produce a feeling of euphoria.

Excessive drinking takes a toll on society as a whole, costing an estimated $249 billion a year, according to the Centers for Disease Control and Prevention.

Dr. Walker and his USF Health team focus on a less studied opioid receptor called the kappa receptor.

They examine what happens in the brain circuitry when the alcohol-induced release of “feel bad” peptides called dynorphins activate kappa opioid receptors. Their preclinical research has shown that abnormal regulation of this dynorphin/kappa-opioid receptor system through excessive drinking can stimulate dysphoria associated with negative emotional states like depression and anxiety, as well as impaired motivation, judgement and decision-making, Dr. Walker said.

“It’s hard to stop drinking once a person achieves a particular pattern of heavy use,” he said. “By blocking some of the dysphoria that drives excessive alcohol use, we’re incorporating a new modality that may achieve better long-term success in stopping alcoholism.”

Dr. Walker with his research team

Brain changes and maladaptive behaviors

Although Dr. Walker’s research centers on alcohol use disorders, the work has relevance for a wide range of addictions.

“Our group and others have shown that the progressive dysregulation that occurs in the brain can extend to all drugs of abuse, whether it be opiates like heroin, or psychostimulants like cocaine and nicotine,” he said. “Whatever the addictive disorder, many of the exact same physical changes happen in the brain to cause a person to adapt in ways that perpetuate self-harm.”

One example of this “maladaptive behavior” is impulsively choosing to consume more alcohol for instant gratification, rather than abstaining from drinking to attain long-term goals. “All these different drugs of abuse activate brain reward systems 50 to 100 times more (powerfully) than anything natural can,” Dr. Walker added. “Instead of having to go out and achieve a long-term goal to get that feeling of euphoria, an individual can inject, smoke or drink something to quickly activate those systems.”

Senior biological scientist Rong (Jennifer) Wang

Many individuals start using alcohol or drugs to get the euphoric ‘feel good’ effects. But the brain normally prefers a set point that balances the highs and lows of mood, so problems arise with misuse, Dr.  Walker said. “The more you artificially create this euphoria, the more intensely the brain fights back by creating dysphoria to equalize the system.”

As alcohol dependence escalates, those who quit drinking in an attempt to stay sober no longer experience the heightened “up” state of euphoria – but all the negative feelings of dysphoria, the “down” state, remain and become more pronounced, he added.  “So, they frequently end up drinking again to self-medicate the depression and anxiety that occurs during withdrawal.”

A major obstacle to recovery — even months or years after rehabilitation and prolonged abstinence – appears to be physical changes in neurotransmitters and their receptor targets as the brain adapts to drugs of abuse.

“Depending on how long or how intensely someone has used alcohol or other drugs of abuse, the dysregulation of the dynorphin-kappa opioid receptor system can persist long after someone stops using,” Dr. Walker said. “Certain environmental cues, like seeing or smelling something associated with prior misuse, may reactivate the dysphoria and cause a relapse.”

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The “one-two” punch of alcoholism

In a key paper published in Biological Psychiatry (2014) titled “The one-two punch of alcoholism,” Dr. Walker and colleagues demonstrated that the dynorphin-kappa opioid receptor system is dysregulated in the amygdala of rats chronically exposed to alcohol. The brain’s amygdala region is vital for many functions, including regulation of emotional behavior and decision-making.

The researchers discovered that dynorphins and signaling by their target kappa opioid receptors both increased in the amygdala, combining to produce a greater (adverse) effect than normal. This combined upregulation underlies the highly maladaptive behavior that promotes continued drinking to temporarily relieve moodiness, anxiety, depression and other dysphoria symptoms, Dr. Walker said.

In the same study, alcohol-dependent rats in acute alcohol withdrawal started to drink like they were nondependent when pharmacological compounds were administered directly into the amygdala to specifically suppress activation of the kappa opioid receptors. The data contributed by Dr. Walker strongly supported the hypothesis that kappa receptor antagonists (blockers) could be a beneficial treatment target for combatting alcohol dependence — in part by preventing a relapse among patients during and soon after withdrawal.

His preclinical work helped determine that kappa opioid receptors were important for the therapeutic effectiveness of nalmefene, a medicine licensed in the European Union to reduce heavy drinking in alcoholic patients who cannot completely abstain.

Gengze Wei, PhD, scientific researcher

Genetics underlying alcohol dependence

Armed with advanced genetic tools, Dr. Walker’s laboratory has also begun exploring ways that genetic variations may work with environmental cues to regulate the neurobehavior (negative emotions, poor judgement and decision-making) that contributes to excessive drinking and relapse.

His group is comparing changes in kappa-opioid receptor gene expression in various brain regions both in alcohol-dependent rats and in their nondependent counterparts. They expect soon to be able to precisely target subtypes of nerve cells involved in shifting the brain’s circuitry from nondependence to dependence. The USF Health researchers plan to mimic the gene expression changes in nondependent rats to observe if they start drinking like dependent rats. They will also block these genetic variations in dependent rats to try to reverse the alcohol-induced maladaptive behavior.

The ability to safely modify specific genes would treat the underlying neurobehavioral causes of alcohol use disorder – not just its symptoms.

The science isn’t there yet. But, Dr. Walker envisions a time when behavioral screening to identify factors that most motivate a person to abuse alcohol or other drugs could be combined with genotyping to help break the addict’s cycle of dependence.

“If we could profile the major genetic and environmental factors that push an individual to continue excessive use, then we could personalize treatment approaches,” he said. “It could help predict how effective a particular treatment would be for an individual patient — and improve the chances of success.”

Stains of dopamine neurons in the midbrain

A White House early career award 

Dr. Walker came to the University of South Florida from Washington State University, where he was an associate professor of psychology.  He was previously a staff scientist for molecular and integrative neurosciences at the Scripps Research Institute in La Jolla, CA.

Dr. Walker received a PhD in neuroscience and behavior from the University of California, Santa Barbara in 2004, and completed postdoctoral research at the Pearson Center for Alcoholism and Addiction Research at Scripps.

He has received numerous distinguished awards, including the 2011 Presidential Early Career Award for Scientists and Engineers presented by President Barack Obama at the White House. The highly competitive PECASE award recognizes exceptional potential for leadership at the frontiers of scientific knowledge.

Continuously funded by the NIH since 2001, Dr. Walker has authored 36 papers in peer-reviewed journals. He served on editorial boards for Neuropsychopharmacology and Honors in Higher Education and as a grants reviewer for the NIH Molecular Neuropharmacology and Signaling (MNPS) study section. He is a member of the American College of Neuropsychopharmacology, the Research Society on Alcoholism and the Society for Neuroscience. 

The 2011 Presidential Early Career Award for Scientists and Engineers, presented to Dr. Walker at the White House, recognizes exceptional potential for leadership at the frontiers of scientific knowledge.

Some things you may not know about Dr. Walker 

• Walker and his wife Jennifer Walker, an IRB research compliance administrator at USF, are both certified scuba divers. They look forward to combining scuba diving with sailing along Florida’s Gulf Coast on his family’s Irwin Ketch called “Peregrine.”
• As a boy in Los Angeles, Dr. Walker hiked to the landmark Hollywood Hills sign overlooking downtown LA, climbing to the top of its white capital letters to take in the view.

-Video by Allison Long, and photos by Freddie Coleman, USF Health Communications and Marketing